Technical Field
The present invention relates to a novel medicine useful for the prevention and treatment of complications after cataract surgery such as secondary cataract and anterior capsule contraction.
Related Art
The crystalline lens refracts light entering into the eye to form an image on the retina and is responsible for the image formation system with the cornea. The anterior surface touches the posterior iris surface through the aqueous humor in the posterior chamber and the posterior surface touches the vitreous body. The crystalline lens is a transparent avascular tissue, and surrounded with a transparent thin membrane called the lens capsule. The anterior surface of the lens capsule is called the anterior capsule, the posterior surface is called the posterior capsule, and the part of the disc edge is called the equator. The zonule of Zinn connects the equator, and is involved in regulating the thickness of the crystalline lens.
The lens epithelial cells line the inside of the lens capsule, and cell division is observed near the equator (epithelial cells in the proliferative zone). The epithelial cells in the equator take the form of an elongated rectangle to differentiate into fiber cells, which are extended to the posterior capsule, transferred towards the central part of the crystalline lens, compressed to the central part of the crystalline lens and dehydrated to form the nucleus of the crystalline lens. As described above, the posterior capsule is fibers, and different from the anterior capsule in this respect. In general, the lens epithelial cells are moderately proliferated, and it is believed that the crystalline lens become heavier and thicker with increasing age.
In addition, spinelike processes, ridge processes and gap junctions exist between fiber cells into which epithelial cells are differentiated, and when there are abnormalities in epithelial cell division and abnormalities in extension to the posterior capsule, opacification due to lens fibers can occur.
Cataracts are caused by lens opacity, and, because incident light is scattered by lens opacity, symptoms such as blurred vision, double vision and intolerance of light emerge, and visual acuity is reduced with progression and cannot be corrected even with eyeglasses. The causes of cataract include congenital conditions, external injuries, atopy, drugs, radiation and the like; however, most of the cataracts are caused by aging, which are generally called senile cataract (age-related cataract) and are believed to be mainly caused by the progression of cortical opacity (cortical cataract) and nuclear sclerosis (nuclear cataract). The surface of light which passes through the crystalline lens varies depending on the size of the pupil, and thus when opacification occurs in the site through which light does not pass, there are almost no subjective symptoms. When observing the crystalline lens in a pupil dilation test (mydriasis test), however, cataracts are detected in people in their forties in the earlier cases, and in the majority of people in their eighties.
In the very early stage of cataract, the progression can be delayed with an ophthalmic preparation in some cases; however, the crystalline lens in which opacification has occurred once cannot be recovered, and for advanced cataract, a method in which the nucleus and cortex of the opaque crystalline lens are removed by a surgical operation (extracapsular lens extraction) and an intraocular lens is inserted is generally carried out. An example thereof is a method in which the anterior surface of the lens capsule (anterior capsule) is incised in a circular manner, the contents in the capsule are fragmented with ultrasonic and sucked, and an intraocular lens is inserted into the remaining capsule, and inserting an intraocular lens becomes easy by leaving the capsule.
This operation hardly causes pain, ends in a relatively short time, and restores visual acuity by inserting an intraocular lens, and thus has been used as a method for treating cataract. It is also said that the disease rate of senile cataract is 60 to 70% in people in their sixties and further almost 100% in people in their eighties or older. In the present situation in which aging society progresses, the importance of the treatment of cataract has increasingly risen, and operation methods and intraocular lenses have been improved.
After a period of time after the operation, however, the crystalline lens can become turbid again by, for example, the proliferation and transfer to the posterior capsule of the lens cells remaining in the capsule. When the opacification progresses, visual function declines and cataract symptoms emerge in some cases. This is called “secondary cataract”, and the incidence rate is reported to be above 19%. However, a complete method for preventing and treating secondary cataract has not been established until now.
As the onset mechanism of secondary cataract, it is mainly believed that posterior capsule opacification (PCO) arises by the migration to the posterior capsule and proliferation of the remaining lens epithelial cells which have not been completely removed by extracapsular lens extraction, or Soemmerring's ring cataract, which has a ring-shaped opacity, and Elschnig's pearls, which have a pearl-like opacity, are formed by, for example, the abnormal proliferation of lens epithelial cells remaining in the equator. It is impossible to completely remove lens epithelial cells in a cataract operation and it is difficult to completely prevent secondary cataract. It is demanded that a medicine for the prevention and treatment of secondary cataract be developed.
In addition, the window of the lens capsule obtained by incising the anterior surface of the lens capsule (anterior capsule) in a circular manner in the cataract operation described above becomes small after the operation in some cases. Such symptom is called “anterior capsule contraction”. This occurs because the lens cells remaining around the incised window are changed to fibrous cells by for example an inflammatory reaction and proliferated to narrow the incised circular window as a purse. This does not normally affect visual function in most cases; however, when the size of the window is increased to cover the central part of the pupil, light is difficult to enter into the eyes, which causes a declined visual function. The “anterior capsule contraction” is also a disease occurring after a cataract operation, and an effective method for the prevention and treatment thereof has not been developed as is the case with secondary cataract, and it is demanded that a medicine for the prevention and treatment of anterior capsule contraction be developed.
Various substances have been reported as secondary cataract inhibitors. It has been for example reported that N-(3,4-dimethoxycinnamoyl)anthranilic acid (general name: Tranilast) known as a therapeutic agent for allergic diseases such as bronchial asthma and allergic rhinitis is used (see WO 98/16214 A), ethylenediaminetetraacetic acid is used as a sustained release preparation (see JP 8-175984 A), transforming growth factor-β (TGF-β) is used (see JP 8-502033 W), a sustained release preparation including, e.g. a 2-piperazinone derivative having a nonpeptidic inhibitory activity on cell adhesion and a polymer is used (see JP 9-235239 A), a polypeptide having an inhibitory activity on cell adhesion and a lactic acid-glycolic acid polymer are used (see JP 9-291040 A), a peptide such as Arg-Gly-Asp is used (see JP 10-17487 A), a focal adhesion modulating substance to regulate adhesion between lens epithelial cells and the lens capsule, e.g. an enzyme precursor of serine protease, is used (see JP 2002-502821 W), a polymer to which a cell death receptor ligand such as Fas ligand is fixed is used (see JP 2004-518649 W), and the like.
It has been also reported that H-7, a kind of serine threonine kinase inhibitor, is effective for resolving Soemmerring's ring, but ineffective for posterior capsule opacification (PCO) (see Baohe Tian, et al., J. Ocular Pharm. Ther., 26(6), 2010, 533-539).
In the meantime, it has been reported that Rho kinase (Rho-Associated, Coiled-Coil Containing Protein Kinase: ROCK) inhibitors (hereinafter, also referred to as ROCK inhibitors) such as fasudil and Y-27632 are used for the treatment of for example glaucoma (see e.g. WO 00/09162 A), and it has been also reported that the ROCK inhibitors are useful as a preventive or therapeutic agent for axial myopia (see WO 2010/010702 A).
It has been also reported that ROCK inhibitors, HF (Hydroxyfasudil) and Y-27632, inhibited contraction induced by cytokines such as PDGF-BB and TGF-β2 in bovine lens cells (see Kumiko Hirayama, et al., IOVS, 45(11), 2004, 3896-3903), ROCK inhibitors, Y-27632, HA-1077, H-1152 and ML-7, inhibit the transdifferentiation and contraction of myofibroblasts induced by TGF-β, which are useful for postoperative scars of glaucoma filtration surgery (see Tobias Meyer-ter-Vehn, et al., IOVS, 47(11), 2006, 4895-4904), a ROCK inhibitor, Y-27632, does not promote proliferation but promotes adhesive properties, and is useful as an anti-scar agent after glaucoma filtration surgery (see Megumi Honjo, et al., IOVS, 48(12), 2007, 5549-5557), and a ROCK inhibitor, fasudil, inhibits hyalocyte-containing collagen gel contraction and is useful for the treatment of vitreoretinopathy (see Takeshi Kita, et al., PNAS, 105(45), 2008, 17504-17509).
It has not been reported, however, that ROCK inhibitors are useful for the prevention and treatment of complications after cataract surgery such as secondary cataract and anterior capsule contraction.